Genetics of glutamate and its receptors in autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental impairment characterized by deficits in social interaction skills, impaired communication, and repetitive and restricted behaviors that are thought to be due to altered neurotransmission processes. The amino acid glutamate is an essential excitatory neurotransmitter in the human brain that regulates cognitive functions such as learning and memory, which are usually impaired in ASD. Over the last several years, increasing evidence from genetics, neuroimaging, protein expression, and animal model studies supporting the notion of altered glutamate metabolism has heightened the interest in evaluating glutamatergic dysfunction in ASD. Numerous pharmacological, behavioral, and imaging studies have demonstrated the imbalance in excitatory and inhibitory neurotransmitters, thus revealing the involvement of the glutamatergic system in ASD pathology. Here, we review the effects of genetic alterations on glutamate and its receptors in ASD and the role of non-invasive imaging modalities in detecting these changes. We also highlight the potential therapeutic targets associated with impaired glutamatergic pathways.

Fig. 1. Glutamate signaling.

Glutamate stored in pre-synaptic vesicles is removed for conversion into glutamine via reuptake by SLC1A into the pre-synaptic terminal or via uptake into glial cells. Glutamate re-enters pre-synaptic vesicles through SLC17A. Glutamine from glial cells has no neurotransmitter activity and is converted back to glutamate by GLS. The ionotropic glutamate receptors (iGluRs) (e.g., GRIN, GRIA, GRIK, and GRID) transport Na⁺ cations into the cell, resulting in Na⁺-mediated depolarization and development of excitatory post-synaptic potential (EPSP) in the post-synaptic membranes. Then, Ca₂⁺ transport leads to the activation of Ca₂⁺-dependent enzymes and ultimately to long-term post-synaptic modification. The mGluRs coupled with G proteins mediate intracellular signal transduction. GRM1 and GRM5 are related to changes in Ca₂⁺ concentrations. GRM2, GRM3, GRM6, and GRM8 inhibit cAMP production. GRM7 prevents glutamate release from pre-synaptic vesicles.

Fig. 2. Distribution and amino acid location of mutations in ionotropic (GRIN1, GRIK5, GRIK4, GRIN2B) and metabotropic (GRM5, GRM7, GRM8) receptors.

The data were downloaded using SFARI Gene database for autism spectrum disorder (https://gene.sfari.org/).

Fig. 3. Genes optimal for normal functioning of glutamate receptors, neuronal migration, and synapsis.

Mutations or disruptions in genes optimal for neuronal migration, synapsis, and normal functioning of glutamate receptors can cause neuronal excitability, altered brain volume, and impaired long-term LTP and LTD that lead to various autism-related deficits. MZ marginal zone, CP cortical plate, IZ intermediate zone, SVZ subventricular zone, VZ ventricular zone, LTP long term potentiation, LTD long term depression.

Fig. 4. Potential therapeutic targets for developing drugs or agents targeting the glutamatergic system in autism.

Different glutamatergic mechanisms such as glutamate inhibition, glutamate release, glutamate receptor modulation, and glutamate clearance serve as important targets that can be used for developing novel drugs or agents that can help in rescuing social and behavioral deficits in autism spectrum disorder.